Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder of childhood in the US. As of 2011, approximately 6.4 million children between the ages of 4 and 17 years of age have received a diagnosis of ADHD. Of these individuals, approximately 60% will be prescribed medication and the psychostimulant d,l-methylphenidate (MPH). In 2010, MPH was the most frequently prescribed medication of any type in adolescents aged 12-17 yrs. There is significant variability between individual patients in terms of blood concentrations measured (i.e. pharmacokinetics [PK]), clinical response, and adverse effects in individuals on the same dosage. Some severe adverse drug reactions (ADRs)-including sudden cardiac death--have been associated with MPH, although the precise reasons for these associations remain controversial. Up to 35% of AHDH patients do not respond satisfactorily to MPH therapy. Presently, there is no specific test or biomarker predictive of who will have a positive or negative response to or adverse effects from MPH treatment. The major hepatic enzyme carboxylesterase 1 (CES1) is responsible for MPH metabolism/deactivation. This project proposes to further identify and characterize genetic variants that affect CES1 expression and activity and reveal key associations between CES1 genotypes and the PK and pharmacodynamics (PD) of MPH in ADHD patients. This project will produce clinically relevant data, with great potential to improve the safety and clinical efficacy of MPH treatment in tens of thousands of patients annually. Study results can quickly be translated and adapted to clinical use in evidence-based strategies applied to drug selection and dosing in patients with ADHD and those medicated with other CES1 substrates.